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Cancer Research Communications Sep 2023Fusobacterium nucleatum (Fn) has been frequently detected in colorectal cancer. A high load of Fn has been associated with subtypes of colorectal cancers, located in the...
UNLABELLED
Fusobacterium nucleatum (Fn) has been frequently detected in colorectal cancer. A high load of Fn has been associated with subtypes of colorectal cancers, located in the proximal colon, exhibiting microsatellite instability-high (MSI-H), MLH1 promoter hypermethylation, the CpG island hypermethylation phenotype-high, or BRAF mutation in some studies. Although these features characterize the sessile serrated pathway (SSP) of colon cancers, other studies have shown that Fn infection is associated with KRAS mutations mainly characteristic of non-serrated neoplasia. It is also not clear at what point the association of Fn infection with these genomic alterations is established during colorectal carcinogenesis. Here we show that MSI-H, MLH1 hypermethylation, BRAF mutation or KRAS mutations were independently associated with Fn infection in colorectal cancer. On the other hand, increasing Fn copy number in tissues was associated with increased probability to exhibit MSI-H, MLH1 hypermethylation or BRAF mutations but not KRAS mutations in colorectal cancer. We also show that Fn load was significantly less than that of colorectal cancer and no association was detected between BRAF/KRAS mutations or MLH1 hypermethylation and Fn infection in adenomas. Our combined data suggest that increasing loads of Fn during and/or after adenomacarcinoma transition might promote SSP but not KRAS-driven colorectal carcinogenesis. Alternatively, Fn preferentially colonizes colorectal cancers with SSP and KRAS mutations but can expand more in colorectal cancers with SSP.
SIGNIFICANCE
The authors demonstrated that Fn is enriched in colorectal cancers exhibiting the SSP phenotype, and in colorectal cancers carrying KRAS mutations. Fn infection should be considered as a candidate risk factor specific to colorectal cancers with the SSP phenotype and with KRAS mutations.
Topics: Humans; Proto-Oncogene Proteins B-raf; Fusobacterium nucleatum; Proto-Oncogene Proteins p21(ras); Colorectal Neoplasms; Adenocarcinoma; Microsatellite Instability; Carcinogenesis
PubMed: 37772997
DOI: 10.1158/2767-9764.CRC-23-0179 -
Clinical Oral Investigations Jun 2024The pathogenesis of oral cavity cancers is complex. We tested the hypothesis that oral microbiota dysbiosis is associated with oral cavity cancer.
OBJECTIVES
The pathogenesis of oral cavity cancers is complex. We tested the hypothesis that oral microbiota dysbiosis is associated with oral cavity cancer.
MATERIALS AND METHODS
Patients with primary oral cavity cancer who met the inclusion and exclusion criteria were included in the study. Matching healthy individuals were recruited as controls. Data on socio-demographic and behavioral factors, self-reported periodontal measures and habits, and current dental status were collected using a structured questionnaire and periodontal chartings. In addition to self-reported oral health measures, each participant received a standard and detailed clinical examination. DNA was extracted from saliva samples from patients and healthy controls. Next-generation sequencing was performed by targeting V3-V4 gene regions of the 16 S rRNA with subsequent bioinformatic analyses.
RESULTS
Patients with oral cavity cancers had a lower quality of oral health than healthy controls. Proteobacteria, Aggregatibacter, Haemophilus, and Neisseria decreased, while Firmicutes, Bacteroidetes, Actinobacteria, Lactobacillus, Gemella, and Fusobacteria increased in oral cancer patients. At the species level, C. durum, L. umeaens, N. subflava, A. massiliensis, and V. dispar were significantly lower, while G. haemolysans was significantly increased (p < 0.05). Major periodontopathogens associated with periodontal disease (P. gingivalis and F.nucleatum) increased 6.5- and 2.8-fold, respectively.
CONCLUSION
These data suggested that patients with oral cancer had worse oral health conditions and a distinct oral microbiome composition that is affected by personal daily habits and may be associated with the pathogenicity of the disease and interspecies interactions.
CLINICAL RELEVANCE
This paper demonstrates the link between oral bacteria and oral cancers, identifying mechanistic interactions between species of oral microbiome.
Topics: Humans; Female; Male; Middle Aged; Dysbiosis; Mouth Neoplasms; Saliva; Case-Control Studies; Surveys and Questionnaires; Aged; Microbiota; Adult; RNA, Ribosomal, 16S; Oral Health
PubMed: 38884817
DOI: 10.1007/s00784-024-05770-8 -
Clinical Oral Investigations Dec 2023To explore the bacterial and inflammatory variations in oral cancer patients with and without jawbone invasion.
OBJECTIVE
To explore the bacterial and inflammatory variations in oral cancer patients with and without jawbone invasion.
MATERIALS AND METHODS
A total of 20 specimens of fresh tumor tissue, including 10 from the tumor-invaded jawbone (JIOC group) and 10 without jawbone invasion (NJIOC group), were collected from oral cancer patients. Meanwhile, 10 specimens from normal oral mucosa were collected from healthy patients (control group). The microbiomic content of each sample was analyzed by 16S rRNA gene sequencing, while the expression of inflammatory cytokines was assessed using protein microarray analysis.
RESULTS
There was a significant difference in β diversity between JIOC and NJIOC groups (P < 0.05), but no difference between NJIOC and control groups. The average relative abundance of Fusobacteria and Spirochaetes was higher, while Firmicutes was lower in the JIOC group than in the NJIOC group (all P < 0.05). The expression of pro-inflammatory cytokines like interleukin (IL)-1α, IL-1β, IL-4, and IL-8 was upregulated in the JIOC group compared with the NJIOC group, while MCP-1 was decreased (all P < 0.05). Slackia spp. and Howardella spp. were positively correlated with IL-4; Odoribacter spp. and Acidaminococcaceae spp. were negatively correlated with IL-4, and Clostridium XIVa spp. was negatively correlated with IL-1α and IL-1β.
CONCLUSION
Bacterial and inflammatory differences were observed in oral cancer patients with and without jawbone invasion, where the relative abundance of the differential bacteria was associated with the expression of the inflammatory cytokines.
CLINICAL RELEVANCE
This study investigated the changes in the flora during jawbone invasion in oral cancer and its effect on inflammatory factors, elucidating the possible mechanisms of jawbone invasion caused by oral cancer, which may lead to new ideas for the clinical prevention and treatment of jawbone invasion in oral cancer.
Topics: Humans; Cytokines; Pilot Projects; RNA, Ribosomal, 16S; Interleukin-4; Mouth Neoplasms; Interleukin-1beta; Interleukin-1alpha; Bacteria
PubMed: 37874389
DOI: 10.1007/s00784-023-05319-1 -
Proteomics. Clinical Applications Sep 2023In this work, we identified human and bacterial proteomes in the saliva from volunteers with gingivitis or healthy.
PURPOSE
In this work, we identified human and bacterial proteomes in the saliva from volunteers with gingivitis or healthy.
EXPERIMENTAL DESIGN
The reported population consisted of 18 volunteers (six with gingivitis and 12 healthy controls). Proteomics characterization was performed using a quantitative mass spectrometry method.
RESULTS
A total of 74 human and 116 bacterial proteins were identified in saliva. The major functional category that was modified in the human proteome was the immune response, followed by transport and protease inhibition. In the bacterial proteome, most of the proteins identified were from the Fusobacteria phylum, followed by Chlamydiae and Spirochaetes.
CONCLUSIONS AND CLINICAL RELEVANCE
We observed statistically relevant differences in the data between the groups. The 15 most important human proteins affecting the variation between case and control groups included cystatin S, alpha amylase, lactotransferrin, and negative elongation factor E. We found that bacterial proteins from Porphyromonas gingivalis and Fusobacterium nucleatum subsp. nucleatum related to the red and orange complexes were closely correlated with the occurrence of periodontal diseases.
Topics: Humans; Saliva; Proteome; Proteomics; Fusobacterium nucleatum; Brazil; Gingivitis; Bacterial Proteins
PubMed: 36764829
DOI: 10.1002/prca.202200098 -
Journal of Advanced Research Mar 2024Growing evidence has shown the correlation between periodontitis and atherosclerosis, while our knowledge on the pathogenesis of periodontitis-promoting atherosclerosis...
INTRODUCTION
Growing evidence has shown the correlation between periodontitis and atherosclerosis, while our knowledge on the pathogenesis of periodontitis-promoting atherosclerosis is far from sufficient.
OBJECTIVES
Illuminate the pathogenic effects of Fusobacterium nucleatum (F. nucleatum) on intracellular lipid deposition in THP-1-derived macrophages and elucidate the underlying pathogenic mechanism of how F. nucleatum promoting atherosclerosis.
METHODS AND RESULTS
F. nucleatum was frequently detected in different kinds of atherosclerotic plaques and its abundance was positively correlated with the proportion of macrophages. In vitro assays showed F. nucleatum could adhere to and invade THP-1 cells, and survive continuously in macrophages for 24 h. F. nucleatum stimulation alone could significantly promote cellular inflammation, lipid uptake and inhibit lipid outflow. The dynamic gene expression of THP-1 cells demonstrated that F. nucleatum could time-serially induce the over-expression of multiple inflammatory related genes and activate NF-κB, MAPK and PI3K-AKT signaling pathways. The exoprotein of F. nucleatum, D-galactose-binding protein (Gbp), acted as one of the main pathogenic proteins to interact with the Cyclophilin A (CypA) of THP-1 cells and induced the activation of the NF- κB, MAPK and PI3K-AKT signaling pathways. Furthermore, use of six candidate drugs targeting to the key proteins in NF- κB, MAPK and PI3K-AKT pathways could dramatically decrease F. nucleatum induced inflammation and lipid deposition in THP-1 cells.
CONCLUSIONS
This study suggests that the periodontal pathogen F. nucleatum can activate macrophage PI3K-AKT/MAPK/NF-κB signal pathways, promotes inflammation, enhances cholesterol uptake, reduces lipid excretion, and promotes lipid deposition, which may be one of its main strategies promoting the development of atherosclerosis.
Topics: Humans; NF-kappa B; Cyclophilin A; Fusobacterium nucleatum; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; THP-1 Cells; Atherosclerosis; Inflammation; Periodontitis; Lipids; Calcium-Binding Proteins; Monosaccharide Transport Proteins; Periplasmic Binding Proteins
PubMed: 37100345
DOI: 10.1016/j.jare.2023.04.007 -
Journal of Dental Research Feb 2024Dental plaque, a highly structured polymicrobial biofilm, persistently forms in the oral cavity and is a common problem affecting oral health. The role of oral defense...
Dental plaque, a highly structured polymicrobial biofilm, persistently forms in the oral cavity and is a common problem affecting oral health. The role of oral defense factors in either collaborating or disrupting host-microbiome interactions remains insufficiently elucidated. This study aims to explore the role of LL-37, a critical antimicrobial peptide in the oral cavity, in dental plaque formation. Through immunostaining dental plaque specimens, we observed that LL-37 and DNA colocalized in the samples, appearing as condensed clusters. In vitro experiments revealed that LL-37 binds rapidly to oral bacterial DNA, forming high molecular weight, DNase-resistant complexes. This interaction results in LL-37 losing its inherent antibacterial activity. Further, upon the addition of LL-37, we observed a visible increase in the precipitation of bacterial DNA. We also discovered a significant correlation between the levels of the DNA-LL-37 complex and LL-37 within dental plaque specimens, demonstrating the ubiquity of the complex within the biofilm. By using immunostaining on dental plaque specimens, we could determine that the DNA-LL-37 complex was present as condensed clusters and small bacterial cell-like structures. This suggests that LL-37 immediately associates with the released bacterial DNA to form complexes that subsequently diffuse. We also demonstrated that the complexes exhibited similar Toll-like receptor 9-stimulating activities across different bacterial species, including , , , and . However, these complexes prompted dissimilar activities, such as the production of IL-1β in monocytic cells via both NLRP3 pathway-dependent and pathway-independent mechanisms. This study, therefore, reveals the adverse role of LL-37 in dental plaque, where it binds bacterial DNA to form complexes that may precipitate to behave like an extracellular matrix. Furthermore, the unveiled stimulating properties and species-dependent activities of the oral bacterial DNA-LL-37 complexes enrich our understanding of dental plaque pathogenicity and periodontal innate immune responses.
Topics: Humans; DNA, Bacterial; Dental Plaque; Porphyromonas gingivalis; Fusobacterium nucleatum; DNA
PubMed: 38093556
DOI: 10.1177/00220345231210767 -
PloS One 2024Crohn's disease (CD) entails intricate interactions with gut microbiome diversity, richness, and composition. The relationship between CD and gut microbiome is not...
Crohn's disease (CD) entails intricate interactions with gut microbiome diversity, richness, and composition. The relationship between CD and gut microbiome is not clearly understood and has not been previously characterized in Saudi Arabia. We performed statistical analysis about various factors influencing CD activity and microbiota dysbiosis, including diagnosis, treatment, and its impact on their quality of life as well as high-throughput metagenomic V3-V4 16S rRNA encoding gene hypervariable region of a total of eighty patients with CD, both in its active and inactive state with healthy controls. The results were correlated with the demographic and lifestyle information, which the participants provided via a questionnaire. α-diversity measures indicated lower bacterial diversity and richness in the active and inactive CD groups compared to the control group. Greater dysbiosis was observed in the active CD patients compared to the inactive form of the disease, showed by a reduction in microbial diversity. Specific pathogenic bacteria such as Filifactor, Peptoniphilus, and Sellimonas were identified as characteristic of CD groups. In contrast, anti-inflammatory bacteria like Defluviitalea, Papillibacter, and Petroclostridium were associated with the control group. Among the various factors influencing disease activity and microbiota dysbiosis, smoking emerged as the most significant, with reduced α-diversity and richness for the smokers in all groups, and proinflammatory Fusobacteria was more present (p<0.05). Opposite to the control group, microbial diversity and richness were lower in CD participants of older age compared to younger ones, and male CD participants showed less diversity compared to women participants from the same groups. Our results describe the first report on the relationship between microbiota and Crohn's disease progress in Saudi Arabia, which may provide a theoretical basis for the application of therapeutic methods to regulate gut microbes in CD.
Topics: Humans; Crohn Disease; Gastrointestinal Microbiome; Saudi Arabia; Male; Female; Adult; RNA, Ribosomal, 16S; Middle Aged; Dysbiosis; Young Adult; Bacteria; Case-Control Studies; Quality of Life
PubMed: 38656971
DOI: 10.1371/journal.pone.0299749 -
Medicina Oral, Patologia Oral Y Cirugia... Sep 2023Studies try to explain the hypothesis that maternal periodontitis may be associated with preterm birth.
BACKGROUND
Studies try to explain the hypothesis that maternal periodontitis may be associated with preterm birth.
MATERIAL AND METHODS
This is a case-control study with 120, 40 cases (gestational age <37 weeks) and 80 controls (gestational age ≥37 weeks), that were submitted to the clinical periodontal examination and subgingival biofilm collection. Bacterial DNA of subgingival biofilm was performed and processed by qPCR.
RESULTS
Periodontitis was statistically significant in the Case group (35%) when compared to the Control group (11.2%) and Gingival Bleeding Index (GBI), sites with PS ≥ 4mm and sites with CAL ≥ 5mm were statistically higher in the Case group (p < 0.05). The proportions of Pi (p = 0.026) and Fn (p = 0.041) of subgingival biofilm were higher in the Case group. A greater number of sites with PS ≥ 4mm (r = -0.202; p = 0.026) and CAL ≥ 5mm (r = -0.322; p < 0.001) were correlated to lower gestational age.
CONCLUSIONS
Periodontitis, preterm delivery, and/or low birth weight may have a possible relationship based on clinical parameters and the ratio of Pi and Fn at periodontal sites.
Topics: Infant, Newborn; Humans; Female; Infant; Fusobacterium nucleatum; Prevotella; Case-Control Studies; Premature Birth; Periodontitis
PubMed: 37622431
DOI: 10.4317/medoral.25874 -
Frontiers in Microbiology 2024Cryoconite is a granular structure present on the glaciers and ice sheets found in polar regions including the Himalayas. It is composed of organic and inorganic matter...
Cryoconite is a granular structure present on the glaciers and ice sheets found in polar regions including the Himalayas. It is composed of organic and inorganic matter which absorb solar radiations and reduce ice surface albedo, therefore impacting the melting and retreat of glaciers. Though climate warming has a serious impact on Himalayan glaciers, the biodiversity of sub-glacier ecosystems is poorly understood. Moreover, cryoconite holes are unique habitats for psychrophile biodiversity hotspots in the NW Himalayas, but unfortunately, studies on the microbial diversity of such habitats remain elusive. Therefore, the current study was designed to explore the bacterial diversity of the Hamtah Glacier Himalaya using both culturable and non-culturable approaches. The culturable bacterial count ranged from 2.0 × 10 to 8.8 × 10 colony-forming units (CFUs)/g at the different locations of the glacier. A total of 88 bacterial isolates were isolated using the culturable approach. Based on the 16S ribosomal RNA gene (16S rRNA), the identified species belong to seven genera, namely, , and . In the non-culturable approach, high-throughput sequencing of 16S rRNA genes (using MiSeq) showed unique bacterial community profiles and represented 440 genera belonging to 20 phyla, namely, Proteobacteria, Actinobacteria, Firmicutes, Bacteroidetes, Chloroflexi, Acidobacteria, Planctomycetes, Cyanobacteria, Verrucomicrobia, Spirochaetes, Elusimicrobia, Armatimonadetes, Gemmatimonadetes, Deinococcus-Thermus, Nitrospirae, Chlamydiae, Chlorobi, Deferribacteres, Fusobacteria, Lentisphaerae, and others. High relative abundances of Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes were observed in the samples. Phototrophic (Cyanobacteria and Chloroflexi) and nitrifier (Nitrospirae) in bacterial populations indicated sustenance of the micro-ecosystem in the oligotrophic glacier environment. The isolates varied in their phenotypic characteristics, enzyme activities, and antibiotic sensitivity. Furthermore, the fatty acid profiles of bacterial isolates indicate the predominance of branched fatty acids. Iso-, anteiso-, unsaturated and saturated fatty acids together constituted a major proportion of the total fatty acid composition. High cold-adapted enzyme activities such as lipase and cellulase expressed by (KY783365) and protease and cellulase activities by . strains (KY783373, KY783377-79, KY783382) provide evidence of the possible applications of these organisms. Additionally, antibiotic tests indicated that most isolates were sensitive to antibiotics. In conclusion, the present study contributed for the first time to bacterial diversity and biopotentials of cryoconites of Hamtah Glacier, Himalayas. Furthermore, the cold-adapted enzymes and polyunsaturated fatty acids (PUFAs) may provide an opportunity for biotechnology in the Himalayas. Inductively coupled plasma mass spectrometry (ICPMS) analyses showed the presence of several elements in cryoconites, providing a clue for the accelerating melting and retreating of the Hamtah glacier.
PubMed: 38751720
DOI: 10.3389/fmicb.2024.1362678 -
Aging Nov 2023Evidence suggests that the tumor microenvironment (TME) affects the tumor active response to immunotherapy. Tumor angiogenesis is closely related to the TME....
BACKGROUND
Evidence suggests that the tumor microenvironment (TME) affects the tumor active response to immunotherapy. Tumor angiogenesis is closely related to the TME. Nonetheless, the effects of angiogenesis on the TME of colorectal cancer (CRC) remain unknown.
METHODS
We comprehensively assessed the angiogenesis patterns in CRC based on 36 angiogenesis-related genes (ARGs). Subsequently, we evaluated the prognostic values and therapeutic sensitivities of angiogenesis patterns using multiple methods. We then performed the machine learning algorithm and functional experiments to identify the prognostic key ARGs. Ultimately, the regulation of gut microbiota on the expression of ARGs was further investigated by using whole genome sequencing.
RESULTS
Two angiogenesis clusters were identified and angiogenesis cluster B was characterized by increased stromal and immunity activation with unfavorable odds of survival. Further, an ARG_score including 9 ARGs to predict recurrence-free survival (RFS) was established and its predominant predictive ability was confirmed. The low ARG_score patients were characterized by a high mutation burden, high microsatellite instability, and immune activation with better prognosis. Moreover, patients with high KLK10 expression were associated with a hot tumor immune microenvironment, poorer immune checkpoint blocking treatment, and shorter survival. The experiments also indicated that () infection significantly induced KLK10 expression in CRC.
CONCLUSIONS
The quantification of angiogenesis patterns could contribute to predict TME characteristics, prognosis, and individualized immunotherapy strategies. Furthermore, our findings suggest that may influence CRC progression through ARGs, which could serve as a clinical biomarker and therapeutic target for -infected CRC patients.
Topics: Humans; Prognosis; Immunotherapy; Algorithms; Cardiovascular Physiological Phenomena; Fusobacterium nucleatum; Tumor Microenvironment; Colorectal Neoplasms
PubMed: 37938164
DOI: 10.18632/aging.205189